ACUTE EFFECTS OF CARBOXYATRACTYLOSIDE AND STEVIOSIDE, INHIBITORS OF MITOCHONDRIAL ADP/ATP TRANSLOCATION, ON RENAL-FUNCTION AND ULTRASTRUCTURE IN PENTOBARBITAL-ANESTHETIZED DOGS

To assess the direct renal toxicity of carboxyatractyloside (CATR), it was administered in relatively low intravenous (i.v.) doses (6.5 and 13.0-mu-mol/kg) to pentobarbital-anesthetized dogs that were being mechanically ventilated in order to circumvent severe extrarenal effects, such as hypoxemia, that could contribute to its nephrotoxicity. Within 2 h post-CATR, site-specific renal damage was noted in S2 and S3 cells of the proximal tubules; characteristic lesions in both cell types included loss of brush border, condensation of mitochondria and proliferation of small vesicles. Other S2 cells exhibited intense staining and reduced cell height. In 3 of 14 CATR-treated dogs, extrarenal effects were of sufficient magnitude to induce cellular swelling and occlusion of tubular lumina in S3 and thick ascending limb segments. Stevioside (STEV), related to CATR in structure and actions on the mitochondrial ADP/ATP translocase, was totally devoid of acute extrarenal or direct renal effects during the 6-h period following intravenous administration of 2.5 times the higher dose of CATR. The ability of CATR to produce renal toxicity via its renal and extrarenal actions emphasizes the importance of minimizing the latter actions of any toxicant when attempting to ascertain the mechanism by which it adversely affects renal function and ultrastructure.